Toxicity of benzodiazepines in the treatment of insomnia disorders in older adults: a systematic literature review

Aim To review the literature data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and determine whether benzodiazepine anxiolytics or hypnotics were more frequently implicated in the cases of abuse and poisoning. Methods We searched PubMed and Scopus for relevant studies published from January 1, 2013, to May 1, 2023. Twelve studies were included in the final selection. Results The review highlights the diverse prevalence rates of benzodiazepine abuse and poisoning in the older adult population. Benzodiazepine anxiolytics were more frequently associated with negative outcomes than benzodiazepine hypnotics. Concurrent use of benzodiazepines, benzodiazepine-related medications, and opioids was reported, although these medications were not the only ones commonly used by the elderly. Conclusion It is essential to increase awareness about adhering to prescribed pharmacological therapies to mitigate issues related to drug abuse and poisoning among older adults.


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Insomnia is a substantial public health concern (1).The International Classification of Sleep Disorders, third edition (IC-SD-3), defines insomnia as a persistent difficulty with falling asleep, maintaining sleep, or reduced quality of sleep, occurring despite adequate opportunities and conditions for sleep.It is a recognized risk factor for impaired daily functioning, substance abuse, depression, other psychiatric disorders, chronic pain, and various other health issues, including obesity, high blood pressure, cardiovascular diseases, and dementia (2).Effective treatment of insomnia is particularly vital in older adults, where age-related changes in sleep, such as circadian rhythm dysregulation and changes in sleep architecture, can aggravate the condition (3).
Benzodiazepines are among several medications for insomnia treatment approved by the United States Food and Drug Administration (4).Only short-term pharmacotherapy for insomnia is recommended, typically lasting four to five weeks (5,6).Prolonged use of medications can lead to dependence.Additionally, using medications in doses inconsistent with prescribed therapy can also lead to dependence (7).
Benzodiazepines are safe and effective when prescribed and used judiciously (8).Nonetheless, in prescribing these medications for older adults with insomnia, it is crucial to consider age-related pharmacokinetic changes, like altered drug metabolism (9) and pharmacodynamic shifts.For example, alterations in the GABA neurotransmitter system lead to increased sensitivity to adverse effects, including ataxia, sedation, and cognitive impairments (10).In this regard, potential issues may arise concerning medication abuse and poisoning among older adults, involving adverse effects, and, in severe cases, leading to death (11).This is particularly relevant as the elderly often concurrently use multiple medications (12).
The clinical manifestations of benzodiazepine poisoning are often more severe in older individuals, frequently leading to coma and increased incidence of complications and longer hospital stays (13).More cases of respiratory failure were reported in older patients; however, there was no significant difference between the groups of older and younger patients.These outcomes may be attributed to age-related pharmacokinetic changes or heightened sensitivity due to compromised organ function, comorbidities, and drug interactions.
The aim of this study is to systematically review the existing literature on the prevalence of benzodiazepine abuse and poisoning in older adult population with insomnia.
We aimed to obtain data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and investigate whether abuse and poisoning occurred more frequently with benzodiazepine hypnotics or benzodiazepine anxiolytics.

MethodS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used as a guideline for writing and reporting.Publication scanning was conducted for a specified time period through an electronic search of the PubMed and Scopus databases.

Inclusion criteria
Studies were selected based on the following inclusion criteria: 1. Study sample: older adults, aged 61 and above.
3. Medication: treatment for insomnia with benzodiazepines, either solely or in combination with other insomnia medications.
4. Study types: controlled clinical studies, randomized controlled trials, descriptive and cross-sectional studies, cohort studies, and case studies.We searched the PubMed and Scopus databases for relevant literature published from January 1, 2013, to May 1, 2023.A uniform search string was employed in both databases: "benzodiazepine and (elderly or 'older adult*' or senior*) and insomnia and (overdose or misuse or abuse or intoxication or poisoning)".

Search strategy
The publication selection involved a three-step process (Figure 1).Initially, 151 articles were identified (126 after removing duplicates) using a predefined search string across PubMed and Scopus databases.After title screening, 51 articles were excluded.In the second step, we examined the abstracts of the remaining articles and, excluded further 56 articles.The full texts of the remaining 19 articles were assessed, resulting in the inclusion of 12 articles (Table 1).

Coding
Data were gathered on the name of the first author, publication year, specific age groups of the older adults in-volved, concurrent use of different benzodiazepine types or other medications, specific benzodiazepines investigated, categorization of hypnotics vs anxiolytics, adverse drug effects examined, confirmation of insomnia treatment, and key findings (Table 1).
Our coding framework encompassed four primary categories derived from the included studies: sociodemographic data (age), diagnosis/treatment of insomnia, pharmacological treatment (involving benzodiazepines or benzodiazepines with other medications), and adverse outcomes associated with these medications.

Review of literature
Out of 126 hits remaining after removing duplicates, we examined publications at two levels (review of titles and abstracts).Using the designated search string, we thoroughly reviewed the content of 19 studies.Among these, three were excluded due to unsuitable sample characteristics, and one was excluded for being a literature review.Despite potential relevance, two studies were further ex-

Main findings
Intoxications with benzodiazepines in the elderly.Potential poisoning may occur as a result of simultaneous use of multiple medications.Ray et al (15) observed that the simultaneous use of benzodiazepines with opioids and benzodiazepine-related medications in individuals aged 65 and above correlated with increased outpatient and overall mortality.
Even after excluding deaths due to overdose, the simultaneous use still resulted in more than a 2-fold increase in overall mortality among the elderly, signifying a health risk.The potential for benzodiazepine poisoning was also highlighted in the case study by Cremaschi al (16), which reported on a 70-year-old man who attempted suicide by overdosing on benzodiazepines and ended up in a coma.Kay et al (17) also noted a link between benzodiazepine use and suicide attempts, although they indicated that suicide attempts could not be solely attributed to benzodiazepine use.

Abuse of benzodiazepines among the elderly.
Benzodiazepine abuse rates among the elderly were as high as 58.6% in those over 61 (19).El Zahran et al (19) reported a slightly lower rate of 47.8% for abuse or inappropriate medication use among the elderly aged 66 and above.Similarly, Díaz-Gutiérrez et al (20) found that 40.6% of older adults consumed a daily dose that was higher than the defined or recommended, and Niznik et al (21)

Secondary findings
Simultaneous use of medications.Studies primarily reported on the concurrent use of benzodiazepines, benzo- diazepine-related medications, and opioids (14)(15)(16)20,21).Studies reporting on the average intake of medications in the elderly indicated, for example, the simultaneous use of two different medications (23) or an average of 5.6 different medications (20).The mentioned studies revealed that the majority of participants were taking one type of benzodiazepine or benzodiazepine-related medication, while some were taking two or even three.Most of the participants in the study by El Zahran et al (19) reported various comorbidities (eg, hypertension, coronary artery disease, cancer, thyroid disease, benign prostatic hyperplasia, migraines, diabetes, lung diseases, arrhythmias, autoimmune diseases, epilepsy, dyslipidemia, kidney diseases, fibromyalgia, and other illnesses), necessitating the use of multiple concurrent medications.
Anxiolytics and hypnotics.Although the findings were somewhat inconsistent, misuse and poisoning were slightly more strongly associated with the use of anxiolytics (14,16,(19)(20)(21).Most studies reported that abuse and poisoning were associated with the use of anxiolytics, particularly alprazolam, diazepam, lorazepam, and clonazepam.The use of other anxiolytics like bromazepam, chlordiazepoxide, oxazepam, clorazepate, and ketazolam was also noted.Concerning hypnotics, the studies reported that the abuse and poisoning were associated with the use of hypnotics such as brotizolam, cloxazolam, estazolam, etizolam, flunitrazepam, flurazepam, haloxazolam, loflazepate, lormetazepam, nimetazepam, nitrazepam, quazepam, rilmazafone, triazolam, and temazepam.

dISCuSSIoN
In this study, the rates for inappropriate use of benzodiazepines ranged from relatively low for hypnotics in those over 65 (7) to over 50% in aged over 61 (18).The lowest abuse rate was recorded by Niznik et al (21) in the age group of 90 years and older.This result could be a consequence of the generally low representation of this age group (3.21% of the total sample, with only 25 individuals chronically using benzodiazepines).A relatively high rate of benzodiazepine abuse (58.6%) was recorded by Tahiri et al (18) in the elderly from Kosovo.Researchers from the neighboring country of Albania recorded 76.4% of inappropriate use of these drugs using the same measurement instruments (25).A substantial prevalence was also observed in the elderly aged over 66 in Lebanon (19 14) also reported a relatively low rate of concurrent use of benzodiazepines and related medications in those over 65 (1.8% for men and 1.5% for women).Notably, most studies reported the simultaneous use of benzodiazepines, benzodiazepine-related medications, and opioids (14)(15)(16)20,21), though these are not the only medications commonly used by the elderly (eg, medications for blood pressure, cholesterol, diabetes, etc).Ray et al (15) emphasized the increased non-hospital and overall mortality associated with the simultaneous use of benzodiazepines, benzodiazepine-related medications, and opioids in those over 65, suggesting potential toxicity, especially given the possible subclinical deterioration of liver and kidney function in the elderly (13).A case study by Cremaschi et al (16) reported on a suicide attempt by benzodiazepines poisoning, possibly due to the age-related changes and a lack of emotional support at the end of life.The elderly may be more determined in their suicide attempts than younger individuals (13).
Although the findings were somewhat inconsistent, misuse and poisoning were slightly more strongly associated with the use of anxiolytics (14,16,(19)(20)(21).The www.cmj.hrlatter, in general, represent a group of medications that is more frequently abused (29).Geulayov et al (30) noted the higher toxicity of temazepam, a benzodiazepine hypnotic, and zopiclone or zolpidem compared with diazepam, a benzodiazepine anxiolytic.Regardless of the classification, vigilant monitoring is essential to ensure that the elderly receive appropriate pharmacological therapy.

limitations and potential for further research
A potential limitation of this review is the reliance on only two databases.Incorporating additional databases could yield more studies and provide a more comprehensive view of the topic.Another limitation could also be the disproportionate focus on the studies that investigated abuse or inappropriate use of benzodiazepines, as opposed to poisoning or ingestion of excessive doses of benzodiazepines and potential mortality in the elderly.Further research could involve reviewing the remaining databases and investigating the poisoning or ingestion of excessive doses among the elderly.In the future, more research attention could be dedicated to poisoning resulting from the use of benzodiazepines in conjunction with other common medications frequently taken by the elderly (eg, medications for blood pressure, cholesterol, diabetes, etc.).

Conclusion
The findings of this brief systematic literature review underscore a varying prevalence -from a few percent to over fifty percent -and potential concerns regarding abuse or inappropriate use of benzodiazepine in general, as well as poisoning among older adults.The association of benzodiazepine anxiolytics with benzodiazepine abuse and poisoning was slightly more pronounced compared with that of benzodiazepine hypnotics.These insights underscore the importance of raising awareness about benzodiazepine-related issues in the older adult population and the critical need for adherence to prescribed pharmacological therapies for benzodiazepine use in general.
Funding None.
ethical approval Not required.
declaration of authorship AKKS, VŠ conceived and designed the study; AKKS acquired the data; AKKS, AM analyzed and interpreted the data; AKKS drafted the manuscript; all authors critically reviewed the manuscript for important intellectual content; all authors gave approval of the version to be submitted; all authors agree to be accountable for all aspects of the work.
Competing interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

5 .
Time period: studies conducted in the last 10 years (2013-2023).6. Outcome: instances of benzodiazepine abuse and poisoning 7. Language: Slovenian or English.www.cmj.hrdatabases and search string

tAble 1 .
FIguRe 1. the selection process of studies included in the systematic literature review.Continued.Studies included in the systematic literature review